Controlled release of steroids from sugar coatings

ABSTRACT

A compressed medicinal tablet comprising a tablet core and a sugar coating, said sugar coating containing a dose of a hormonal steroid and a steroid release rate controlling amount of microcrystalline cellulose.

RELATED APPLICATIONS

This application is a continuation-in-part of co-pending applicationSer. No. 08/373,667, filed Jan. 17, 1995, by Reginald J. Barcomb, nowU.S. Pat. No. 5,547,948.

BACKGROUND OF THE INVENTION

In the past three decades, substantial effort has gone into theidentification of methods for controlling the rate of release of drugfrom pharmaceutical tablets. Excipients have been incorporated intotablet cores to control dissolution, and hence absorption, of drugs.Tablets and spheroids have been coated with polymers to provide slow,diffusion--controlled release or site-specific release of drugs.

Tablets and encapsulated spheroid dosage forms have also been preparedcontaining multiple drugs, either in admixture or as separate tabletlayers or spheroids. The drugs are provided to perform multiplefunctions or to provide synergism. Such tablets are especially useful inthose circumstances where conventional therapy dictates the use of morethan one drug possessing different but compatible activities. Forexample, diuretic agents are frequently administered withantihypertensive agents, and progestational agents in conjunction withestrogens.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a pharmaceuticaltablet comprising an internal compressed core and an external sugarcoating, wherein said compressed core optionally contains nopharmacologically-active agent or one or more non-steroidal,pharmacologically-active agents that are conventionally administered inconjunction with a hormonal steroid, the improvement which comprises theincorporation of a hormonal steroid and a hormonal steroid release ratecontrolling amount of micro-crystalline cellulose in said sugar coating.The compressed tablet core may be devoid of any medicament or it maycontain a pharmaceutical agent other than a steroid, that is compatiblewith the steroid and any other therapeutic agent in the sugar coating.Thus, the sugar coated tablets of this invention may contain one or morepharmacologically-active agents, where the improvement in prior sugarcoated tablets comprises the incorporation of a hormonal steroid releaserate controlling amount of microcrystalline cellulose in conjunctionwith a hormonal steroid in said sugar coating. The sugar-coated tabletmay be finished with color coatings and polished as is common in coatedtablets.

The contents of the tablet core are quite independent from the sugarcoating in the sense that the sugar coating and the hormonal steroidcontained in it are dissolved before disintegration of the compressedtablet core and dissolution of any drug component present in the core.The excipient components employed in formulation of the core tablet mayinclude pharmaceutically-acceptable water-soluble and/or insolublesubstances such as lactose, calcium phosphate, starch, calciumcarbonate, dextrose, sorbitol, mannitol, microcrystalline cellulose,sucrose, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose,alginates, hydroxypropylcellulose, hydroxypropylmethyl-cellulose,ethylcellulose, croscarmellose sodium, sodium starch glycolate,magnesium stearate, stearic acid, polyethylene glycol, sodium laurylsulfate, fumed silica, talc and the like.

The sugar coat containing the hormonal steroid also contains a steroidrelease rate-controlling amount of microcrystalline cellulose and, incertain circumstances, polyvinylpyrrolidone to aid in application of thesugar coat.

The tablet core is produced by compression of an admixture, which haspreferably been granulated, of the pharmaceutically-acceptableexcipients, and, if desired, a therapeutic agent compatible with thesteroid to be incorporated with the release rate controlling amount ofmicrocrystalline cellulose in the sugar coating. The tablet core mayhave an unplasticized or plasticized seal coat designed to modify thedrug release characteristics of any drug(s) contained within the core,or to protect them against moisture and/or oxygen. The non-medicatedcores are those conventionally employed as placebo tablets inpharmacological studies.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides an improved compressed tablet in which, inaddition to a conventional internal tablet core optionally containing nodrug or one or more drugs that are pharmacologically compatable with asteroid in the external sugar coating, a sugar coating is present whichcomprises a hormonal steroid in an amount of about 0.1 to about 20percent by weight of the sugar coating; microcrystalline cellulose in anamount from about 0.1 to about 3 percent by weight of the sugar coating;polyvinylpyrrolidone in from about 0 to about 5 percent by weight of thesugar coating; and sugar. On a unit dose basis, the tablet containsabout 0.01 to about 50 milligrams, preferably about 0.015 to about 40milligrams and more preferably about 0.02 to 30 milligrams, of totalhormonal steroid load in the loaded sugar coating layer. If desired, anundercoat of inert filled sugar may be applied over a seal coat prior tothe steroid loaded sugar coat layer. The inert filler-containingsub-layer sugar coating may be made up with sucrose containing about 7.5to about 15 percent microcrystalline cellulose. The outer sugar coatingmay contain a coloring agent such as titanium dioxide or a primary,secondary or grayed tint as is customary in the tableting art. Ifdesired, the coloring agent may be applied as a separate coating layerover the outer sugar layer. A final polish may be used to further finishand complete the tablet.

The sugar used in production of the sugar coatings referred tothroughout this specification is a sugar product, such as sucrose,derived from beet or cane sources or starch, saccharide orpolysaccharide converted sources, which are considered suitable fortablet coating purposes. The currently preferred sugar is sucrose.

It has been discovered that the release of a hormonal steroid from thesugar coating can be controlled by limiting the quantity ofmicrocrystalline cellulose to from about 0.1 to about 3 percent byweight of the sugar coating. This use of a small quantity ofmicrocrystalline cellulose in the sugar coat is unlike the use of thisexcipient as a compression aid or to assist disintegration of a tabletcore. In the latter case, the concentration of microcrystallinecellulose may rise to as high as 15 to 30 percent of weight.

Examples of hormonal steroids suitable for incorporation into the sugarcoating formulations of this invention include, for instance, one ormore of the following steroids; medroxyprogesterone acetate,levonorgestrel, gestodene, medrogestone, estradiol, estriol,ethinylestradiol, mestranol, estrone, dienestrol, hexestrol,diethylstilbestrol, progesterone, desogestrel, norgestimate,hydroxyprogesterone, norethindrone, norethindone acetate, norgestrel,megestrol acetate, methyltestosterone, ethylestrenol, methandienone,oxandrolone, trimegestone, dionogest, and the like. Additionally, thetissue selective progesterones and/or progesterone antagonists which mayor may not have the typical steroidal functionality may be formulatedinto this technology. These include, but are not limited to: RU-486,onapristone, ZK-137316, ORG-31730, and HRP-2000. Where desired,estrogenic steroids and progestogenic steroids may be used incombination in the sugar coatings.

To illustrate in vitro dissolution rate control of steroid in theabsence and presence of microcrystalline cellulose, the followingillustrative examples are presented, without limitation:

EXAMPLE 1

A sugar coating consisting of the following solids was applied over atablet core using either a non-perforated or perforated coating pan:

    ______________________________________                                        Sucrose, NF           87%                                                     Polyvinylpyrrolidone   3%                                                     Medroxyprogesterone Acetate, USP                                                                    10%                                                     ______________________________________                                    

The rate of dissolution of the steroid was determined in accordance with<711> of USP XX, p.959 (1980), employing Apparatus 2, operating at 50rpm by dissolving in 0.54% sodium lauryl sulfate in water at 37° C. insix repeated trials (Method A). CV represents the coefficient ofvariation between these trials expressed as a percentage.

    ______________________________________                                        Time (min.)                                                                              Percent Steroid Released (CV %)                                    ______________________________________                                         5         93 (5.2)                                                           10         94 (5.3)                                                           30         95 (5.3)                                                           60         95 (5.4)                                                           120        95 (5.4)                                                           ______________________________________                                    

EXAMPLE 2

Tablets coated in the same manner with the same sugar coating as abovewere dissolved in 0.13% sodium lauryl sulfate in 0.1N HCl at 37° C.using USP Apparatus 1 at 100 rpm, in six trials (method B). The resultsof this study were:

    ______________________________________                                        Time (min.)                                                                              Percent Steroid Released (CV %)                                    ______________________________________                                         5         83 (6.0)                                                           10         85 (5.8)                                                           30         85 (6.2)                                                           60         85 (6.1)                                                           120        85 (6.2)                                                           ______________________________________                                    

EXAMPLE 3

Additional tablets coated in the same manner with the same sugarcomposition were subjected to a flow-through dissolution test procedurein 0.12% sodium lauryl sulfate in 0.1N HCl at 37° C. using a SOTAXDissotest Apparatus at 5.7 mL/min. flow rate (Method C). The results ofthree separate runs were as follows:

    ______________________________________                                        Time (min.)                                                                              Percent Steroid Released (CV %)                                    ______________________________________                                         30        90.9 (2.9)                                                          60        94.2 (3.0)                                                          90        95.3 (2.9)                                                         120        96.0 (3.0)                                                         210        97.4 (3.0)                                                         300        98.9 (3.6)                                                         ______________________________________                                    

From these in vitro studies it is clear that medroxyprogesteroneacetate, used here as a typical steroid, is released from the sugarcoating extremely rapidly.

EXAMPLE 4

For comparison purposes, and to illustrate the unexpected properties ofthe sugar coatings of this invention, a sugar coating consisting of thefollowing solids was applied over a tablet core:

    ______________________________________                                        Sucrose, NF          86.5%                                                    Microcrystalline Cellulose                                                                          0.5%                                                    PVP                   3.0%                                                    Medroxyprogesterone Acetate, USP                                                                   10.0%                                                    ______________________________________                                    

Employing the microcrystalline cellulose--containing sugar coatedtablets and following Method A, the following in vitro dissolution datawere obtained from three runs:

    ______________________________________                                        Time (min.)                                                                              Percent Steroid Released (CV %)                                    ______________________________________                                         5         19.5 (49.5)                                                        10         29.9 (32.8)                                                        30         50.0 (23.0)                                                        60         61.6 (19.5)                                                        120        74.2 (19.2)                                                        ______________________________________                                    

EXAMPLE 5

With additional microcrystalline cellulose--containing sugar coatedtablets prepared in the same manner as above, following Method B in sixruns, the following data were obtained:

    ______________________________________                                        Time (min.)                                                                              Percent Steroid Released (CV %)                                    ______________________________________                                         5          2.3 (34.4)                                                        10          8.2 (27.0)                                                        30         17.9 (16.1)                                                        60         26.5 (13.6)                                                        120        32.7 (16.6)                                                        ______________________________________                                    

EXAMPLE 6

And, following method C, with the tablets containing microcrystallinecellulose in the sugar coating, in three runs, the following data wereobtained:

    ______________________________________                                        Time (min.)                                                                              Percent Steroid Released (CV %)                                    ______________________________________                                         30        2.8 (34.4)                                                          60        4.1 (24.8)                                                          90        5.1 (22.3)                                                         120        6.4 (22.3)                                                         210        11.0 (19.4)                                                        300        14.3 (11.0)                                                        ______________________________________                                    

From these data it is apparent that a small amount of microcrystallinecellulose in the sugar coating (in this case 0.5% by weight of the sugarcoating solids) has markedly retard the release rate of hormonalsteroid.

EXAMPLE 7

Sugar coated tablets were prepared in which the sugar coat contained0.0%, 0.5% or 2% microcrystalline cellulose in combination with 3.0%polyvinyl pyrrolidone, 10.0% medroxyprogesterone acetate and sucrose.These tablets were fed to four beagle dogs under fasting conditions andthe blood plasma levels of steroid were determined at 0, 0.5, 1, 1.5, 2,3, 5, 8, 12, 16, and 24 hours. The resulting data were plotted, the areaunder the curve (AUC) calculated for a twenty four hour period and thetime at which the maximum plasma concentration occurred was determinedto be as follows:

    ______________________________________                                        Microcrystalline                                                                          AUC(0-24 Hrs)          Cmax                                       Cellulose % ngxhr/mL      tmax (Hr)                                                                              (ng/mL)                                    ______________________________________                                        0.0         345           0.6      37.8                                       0.5         294           1.0      36.9                                       2.0         294           1.1      24.6                                       ______________________________________                                    

From these in vivo dog data, it is obvious that a marked change inbioavailability of a hormonal steroid occurs as the concentration ofmicrocrystalline cellulose in the sugar coating increases from 0.0 toone containing 0.5 to 2.0% microcrystalline cellulose. Thus, the rate ofrelease of hormonal steroid incorporated in a sugar coating may becontrolled by incorporation of very small amounts of microcrystallinecellulose into sugar coating.

EXAMPLE 8

Sugar coated tablets were prepared in which the sugar coat contained0.25%, 0.5% or 0.8% microcrystalline cellulose in combination with 0.5%polyvinyl pyrrolidone, 5.0% medroxyprogesterone acetate and sucrose.These tablets were subjected to an in vitro dissolution test employingthe USP Disintegration Apparatus (USP XX, <201>, p958) (1980) with a0.54% sodium lauryl sulfate dissolution medium at 37° C. The followingtest data were obtained:

    ______________________________________                                        Percentage Medroxyprogesterone Acetate Dissolved (CV %)                                0.25%       0.5%        0.8%                                                  Microcrystalline                                                                          Microcrystalline                                                                          Microcrystalline                             Time (Minutes)                                                                         Cellulose   Cellulose   Cellulose                                    ______________________________________                                        15       97.8 (5.2)  72.6 (9.5)  32.4 (15.2)                                  30       98.8 (5.3)  89.9 (6.3)  62.8 (8.2)                                   45       99.3 (5.2)  95.2 (5.6)  76.6 (6.9)                                   60       99.1 (5.2)  98.3 (5.7)  84.8 (6.6)                                   90       99.9 (5.3)  100.9 (6.0  94.4 (6.9)                                   120      100.3 (5.6) 102.4 (5.3) 98.0 (7.1)                                   ______________________________________                                    

These dosage forms were also evaluated in a human bioavailability study.The dosage forms were administered in a cross-over design to twelvehealthy female subjects. Blood samples were collected at 0.5, 1, 1.5, 2,2.5, 3, 4.5, 6, 8, and 12 hours and the plasma assayed formedroxyprogesterone acetate. The following data were obtained:

    ______________________________________                                        Microcrystalline                                                              Cellulose AUC (0-12 h) tmax (hr)                                                                              Cmax (ng/mL)                                  ______________________________________                                        0.25%      26.0 ± 14.3*                                                                           2.9 ± 1.3                                                                           4.24 ± 3.0                                  0.5%     25.8 ± 10.5                                                                             3.2 ± 1.2                                                                           3.88 ± 1.87                                 0.8%     13.2 ± 4.0                                                                              3.9 ± 1.6                                                                           1.99 ± 0.73                                ______________________________________                                         *Mean values ± 1 Standard Deviation                                   

From the in vitro dissolution and in vivo human bioavailability data, itis clear that the drug release characteristics and bioavailability ofthe hormonal steroid, are controlled by the concentration ofmicrocrystalline cellulose in the sugar coating.

EXAMPLE 9

A sugar coating containing 5 mg of medrogestone in a matrix of sucrosewith 0.4% microcrystalline cellulose and 0.5% polyvinyl pyrrolidone wasapplied to a sealed and sugar-coated tablet core. The in vitrodissolution profile of this dosage form was compared to that of arapidly-disintegrating compressed tablet containing 5 mg ofmedrogenstone using the dissolution test described in <711> of USP XX,p. 959 (1980) employing Apparatus 2 operating at 50 r.p.m., with 900 mLof 0.54% sodium lauryl sulfate at 37° C. The following data wereobtained:

    ______________________________________                                        Mean Percentage Medrogestone Released (CV %)                                            Conventional  Sugar Coated Tablet                                             Rapidly Disintegrating                                                                      Containing Medrogestone                               Time (Minutes)                                                                          Tablet        in Sugar Coat                                         ______________________________________                                        15        95 (2.0)       6 (11.2)                                             30        95 (2.9)      11 (6.9)                                              45        97 (1.6)      15 (6.4)                                              60        97 (1.9)      18 (6.6)                                              120       98 (1.9)      25 (6.2)                                              ______________________________________                                    

The dramatic effect of reduced dissolution of medrogestone when thehormone is incorporated in a sugar coat containing 0.4% microcrystallinecellulose is clearly demonstrated.

One preferred embodiment of this invention is a compressed tablet inwhich the tablet core contains a unit dose of an estrogenic compound ora mixture thereof in an amount of from about 0.1 to about 5.0milligrams, or more preferably from about 0.3 to about 2.5 milligrams,in combination with standard excipient compression aids and fillers.Most desirably, the conjugated estrogens found in the tablet corecomprise the naturally occurring conjugated estrogen product known asPremarin®. Over a sugar coat on the compressed tablet is applied anadditional sugar coat containing about 1 to about 50 milligrams, andpreferably about 1.5 to about 30 milligrams, of medroxyprogesteroneacetate, a color coat, and finally, a polish coat. In otherapplications, it is preferable to employ a non-medicated core with asugar coating containing a steroid such as trimegestone and morepreferably, a sugar coating containing a mixture of steroids such astrimegestone and a conjugated estrogen.

What is claimed is:
 1. In a pharmaceutical tablet comprising an internalcompressed core and an external sugar coating, wherein said compressedcore optionally contains no pharmacologically-active agent or one ormore non-steroidal, pharmacologically-active agents that areconventionally administered in conjunction with a hormonal steroid, theimprovement which comprises the incorporation of a hormonal steroid anda hormonal steroid release rate controlling amount of micro-crystallinecellulose in said sugar coating.
 2. In a pharmaceutical tabletcomprising a non-medicated, compressed core and a sugar coating, theimprovement comprising incorporating a hormonal steroid and a hormonalsteroid release rate controlling amount of microcrystalline cellulose insaid sugar coating.
 3. A pharmaceutical tablet of claim 1, in which saidsugar present in said coating composition is sucrose.
 4. Apharmaceutical tablet of claim 1 in which said hormonal steroid presentin said sugar coating is medroxyprogesterone acetate, levonorgestrel,gestodene, medrogestone, estradiol, estriol, ethinylestradiol,mestranol, estrone, dienestrol, hexestrol, diethylstilbestrol,progesterone, desogestrel, norgestimate, hydroxyprogesterone,norethindrone, norethindone acetate, norgestrel, megestrol acetate,methyltestosterone, ethylestrenol, methandienone, oxandrolone,trimegestone or dienogest.
 5. A pharmaceutical tablet of claim 1 inwhich said sugar coating comprises sucrose, from about 0.1% to about 3%microcrystalline cellulose, by weight, polyvinylpyrrolidone in an amountof from 0 to about 5% by weight and a hormonal steroid in an amount offrom about 0.1 to about 20% by weight.
 6. A pharmaceutical tablet ofclaim 1 in which said sugar coat contains an estrogenic steroid and aprogestogenic steroid.